Good news on drugs for the battle of "wolf" (SLE) in 2019 (I)

Original: Yaodu consulting Guo Lei team Comments of qiansong Yiguo: Half a century may be the life of some people, but patients with SLE wait half a century for the outbreak of new drugs But if you look at the drugs on the market now, whether they are belimumab, telitacicept or Atacicept, they are all directly targeted at B cells The cross indication rituximab directly and simply kills B cells Anifrolumab and brepocitinib affect the differentiation of immune cells through signal pathway, trying to ultimately affect the differentiation of B cells Finally, they are all right and wrong It is inevitable to alleviate symptoms by partially weakening the immune system Naturally, it will bring about an increase in the risk of infection Biopharmaceutics have become the backbone of this field, but they are also famous for their rapid renewal How to set foot on the latest era, to avoid their own products from the project has become a "dimension reduction hit" varieties, has become a pharmaceutical enterprise must consider In view of the increased risk of infection and other safety problems existing in the listed drugs, the research and development of new drugs in the future is also very simple, reducing side effects! How to achieve this goal, in fact, through the analysis of the whole drugs under research (including pre clinical drugs), we can easily see the historical path of the development of drugs in the whole field, jump out of the current dimension to see the development trend of drugs in this field 2019 is a year full of expectations for Chinese patients with systemic lupus erythematosus In July, belimumab, which was originally developed by GlaxoSmithKline, was approved to be listed in China, followed by telitacicept, which was independently developed by Rongchang biology in China The phase II / III clinical trial for the treatment of systemic lupus erythematosus reached a critical clinical end point and showed good clinical efficacy In September, anifrolumab, developed by AstraZeneca, reached the main end point in the clinical phase III trial (tulip2 study) for the treatment of systemic lupus erythematosus The disease activity with clinical significance was significantly reduced, which may be a choice for Chinese patients in the future On December 6, it was learned from the review center of China food and drug administration that Pfizer's pf-06700841 was used to treat systemic lupus erythematosus and obtained the implied license of nmpa clinical trial In 2018, the global market of systemic lupus erythematosus is about US $1.2 billion, and the Chinese market is about US $200 million Frost & Sullivan expects a compound growth rate of 21.7% from 2019 to 2030 The global market will reach US $14.9 billion and the Chinese market will reach US $2.13 billion by 2030 Belimumab is the only biological drug for the treatment of systemic lupus erythematosus in the world It was first launched in the United States in 2011, with global sales of $106 million in 2012 and $629 million in 2018, with a compound annual growth rate of 28% since its launch The typical symptom of systemic lupus erythematosus (SLE) is the appearance of butterfly like erythema on the face The term lupus comes from the 18th century It is believed that the erythema on the face of SLE is caused by the bite of wolf SLE is an autoimmune disease with strong heterogeneity A large number of autoantibodies are produced in patients, which attack multiple organs and tissues and cause multiple system involvement At present, it is believed that it is caused by the interaction of environment, virus, drugs, hormones and other stimulating factors with polygenes It is estimated that the incidence rate of SLE is about 30~50/100000, which is mostly in women of childbearing age of 15-45 years old, and the incidence rate of females is about 9 times that of men Race is an important factor affecting the incidence rate Among Africans, Asians and Hispanics, the incidence rate and prevalence of SLE are high Besides, they tend to be earlier and more serious At present, there are more than one million patients in China, the prevalence rate is about 70 / 100000, the 5-year survival rate of SLE patients is 94%, and the 10-year survival rate is 89% At present, antimalarial drugs (hydroxychloroquine), glucocorticoids and immunosuppressants are commonly used in SLE Hydroxychloroquine treatment of SLE is beneficial to control the disease, improve the symptoms of lupus nephritis and nervous lupus, reduce the recurrence and improve the survival rate, but in the safety evaluation, it may cause retinal abnormalities Glucocorticoids, such as prednisone, can rapidly inhibit the immune state of the body and relieve clinical symptoms, which is one of the most commonly used drugs in the period of SLE induced remission In the medium and long-term treatment, the hormone should be reduced to prednisone ≤ 7.5mg or the equivalent dose, and the hormone should be stopped gradually as much as possible Glucocorticoids can induce osteoporosis or irreversible organ damage When the curative effect of hydroxychloroquine and glucocorticoid is not good, the combination of immunosuppressants, such as methotrexate or azathioprine, will be considered according to multiple factors such as fertility intention At present, there are mainly rituximab (rituximab) and belimumab Rituximab is a human / mouse chimeric antibody targeting CD20 It can selectively remove the abnormal proliferation of B cells and reduce the production of autoantibodies Rituximab combined with basic therapy can reduce the dosage of glucocorticoids in SLE patients, and the improvement rate of clinical involvement in joints, skin, kidney and blood system is 72%, 70%, 74% and 88%, respectively But at present, there is no safety and effectiveness document of the system Belimumab is used in the first-line treatment of hydroxychloroquine, hormone and immunosuppressive drugs with poor efficacy, or when glucocorticoids cannot be reduced Compared with the traditional treatment, the biological targeted preparation has significant curative effect and little side effect, which is expected by many people At present, there are some problems such as single market varieties and high price In July this year, belimumab was approved by nmpa to go on the market It is the first biological drug for treating SLE in China in 60 years At present, the domestic price is uncertain If the purchase price is $669.42/200mg (subcutaneous administration, once a week) in the United States, the annual cost is about $34905 If the domestic price is calculated as 60% of the sales price in the United States, the annual cost for the domestic patients is about $20943 (without consideration of drug donation, etc.) At present, there is only one bio targeting drug in the world, which obviously cannot meet the needs of about one million SLE patients in China and about five million patients in the world As of November 25, 2019, according to the drug delivery database, there are seven SLE drugs on the market, mainly glucocorticoids, hydroxychloroquine and antimalarial drugs In addition, belimumab was launched in 2011, breaking the embarrassing situation that there was no new drug for more than 50 years in systemic lupus erythematosus The specific information of drugs on the market is shown in the table Table 1 Summary of marketed SLE drugs Belimumab is an all human IgG1 λ monoclonal antibody developed by GlaxoSmithKline (GSK) It was first approved by FDA in March 2011 and used to treat active and auto antibody positive adult SLE patients In April 2019, FDA approved the treatment of children with SLE aged 5 and over who were active and positive for autoantibody In July 2019, it was approved to be listed by China nmpa, and the indication was active autoantibody positive systemic lupus erythematosus that had received standard treatment Belimumab can bind to B lymphocyte stimulating factor (BLyS), prevent BLyS from binding to its receptor on B cell, reduce B cell survival, promote B cell apoptosis, and reduce B cell differentiation to plasma cell secreting antibody There are two dosage forms of drugs for subcutaneous administration or intravenous drip The efficacy evaluation of belimumab intravenous injection was based on a randomized, double-blind, placebo-controlled, adult trial (Trial 1, nct00410384; trial 2, nct00424476) Test 1 showed that belimumab 10mg / kg and standard treatment reached the main efficacy end point: the sri-4 response at the 52nd week was significantly higher than that of placebo (43.2% vs 33.5%; P = 0.017); the ratio of 1mg / kg group was 40.6% (P = 0.089) The results of Experiment 2 showed that the sri-4 response of 1 mg / kg belimumab group was (51% vs 46%%; P = 0.017) and that of 10 mg / kg group was 53%, which was significantly higher than that of placebo group The incidence of adverse events was similar between groups See Table 2 for specific results Table 2 clinical trial results of belimumab intravenous injection In addition, there was a study on the treatment of SLE patients in Northeast Asia by belimumab, led by Peking Union Medical College Hospital, which recruited SLE patients from China, South Korea and Japan The main endpoint was the composite response rate (sri-4) at the 52nd week The results showed that the response rate of sri-4 was higher than that of placebo (53.8% vs 40.1%; 1.99 (95% CI: (1.40, 2.82); P = 0.0001)) Compared with baseline, the percentage of subjects with Selena SLEDAI and sri-7 ≥ 4 scores was significantly higher in the belimumab group than in the placebo group; the daily dose of prednisone ≤ 7.5 mg / day was significantly reduced in the belimumab group (P = 0.0228); the risk of severe SLE was 50% lower in the belimumab group (P = 0.0004) The efficacy evaluation of belimumab subcutaneous injection was based on a randomized, double-blind, placebo-controlled trial (nct01484496) The response rate of sri-4 was 61% in belimumab plus standard treatment group and 48% in placebo plus standard treatment group The secondary efficacy end point was that 18% of the patients receiving belimumab plus standard treatment reduced the average dose of prednisone to ≤ 7.5mg/day between the 40th week and the 52nd cycle, and 12% of the patients receiving placebo plus standard treatment met the standard The median time of the first attack was 171 days in the belimumab plus standard treatment group and 118 days in the placebo plus standard treatment group Table 3 clinical trial results of belimumab subcutaneous injection